title: Behavioral defects in chaperone-deficient Alzheimer's disease model mice.
abstract: Molecular chaperones protect cells from the deleterious effects of protein misfolding and aggregation. Neurotoxicity of amyloid-beta (Aβ) aggregates and their deposition in senile plaques are hallmarks of Alzheimer's disease (AD). We observed that the overall content of αB-crystallin, a small heat shock protein molecular chaperone, decreased in AD model mice in an age-dependent manner. We hypothesized that αB-crystallin protects cells against Aβ toxicity. To test this, we crossed αB-crystallin/HspB2 deficient (CRYAB⁻/⁻HSPB2⁻/⁻) mice with AD model transgenic mice expressing mutant human amyloid precursor protein. Transgenic and non-transgenic mice in chaperone-sufficient or deficient backgrounds were examined for representative behavioral paradigms for locomotion and memory network functions: (i) spatial orientation and locomotion was monitored by open field test; (ii) sequential organization and associative learning was monitored by fear conditioning; and (iii) evoked behavioral response was tested by hot plate method. Interestingly, αB-crystallin/HspB2 deficient transgenic mice were severely impaired in locomotion compared to each genetic model separately. Our results highlight a synergistic effect of combining chaperone deficiency in a transgenic mouse model for AD underscoring an important role for chaperones in protein misfolding diseases.
authors.affiliation: Center for Molecular Chaperones and Radiobiology, Medical College of Georgia, Augusta, Georgia, United States of America.
authors.forename: Juhi
authors.initials: J
authors.lastname: Ojha
authors.forename: Rajalakshmi V
authors.initials: RV
authors.lastname: Karmegam
authors.forename: J Gunasingh
authors.initials: JG
authors.lastname: Masilamoni
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
authors.forename: Anil G
authors.initials: AG
authors.lastname: Cashikar
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D055551:HSP27 Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D008124:Locomotion / Q000235:genetics / Q000502:physiology; D008297:Male; D001523:Mental Disorders / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics; D010147:Pain Measurement; D010805:Physical Conditioning, Animal; D038203:alpha-Crystallin B Chain / Q000235:genetics
chemical_list: C525420:Cryab protein, mouse; D055551:HSP27 Heat-Shock Proteins; C486699:Hspb2 protein, mouse; D018832:Molecular Chaperones; D038203:alpha-Crystallin B Chain